Voltage-dependent calcium channels are a complex of a pore-forming alpha-1 (α1) subunit, an auxiliary alpha-2-delta (α2δ), beta (β) and gamma (γ) subunits [Annual Review of Cell and Developmental Biology, 2000, Vol. 16, p. 521-555]. The α2δ proteins are known to modulate both the calcium channel density and the voltage-dependent kinetics of the calcium channels [Trends in Pharmacological Science, 2007, Vol. 28, p. 220-228].
Gabapentin and pregabalin, derivatives of γ-amino butyric acid (GABA), are reported to be effective for diseases of the central nervous system (CNS), sensory disorders, and the like, and their use as antiepileptic drugs or analgesics are known [Trends in Pharmacological Science, 2007, Vol. 28, p. 75-82]. Because gabapentin and pregabalin have a high affinity to α2δ proteins, it has been suggested that their action on α2δ proteins plays an important role in exhibiting pharmacological effects such as the antiepileptic and analgesic effects [The Journal of Biological Chemistry, 1996, Vol. 271, p. 5768-5776, and Journal of Membrane Biology, 2001, Vol. 184, p. 35-43].
In other words, the compounds having a high affinity to α2δ proteins (α2δ ligands) are considered to be useful as therapeutic and/or preventive agents for diseases such as CNS disease and sensory disorder. Specifically, α2δ ligands are considered to be useful as therapeutic and/or preventive agents for diseases such as pain (including, for example, neuropathic pain, trigeminal neuralgia, diabetic pain, postherpetic neuralgia, phantom pain, neuropathic lower back pain, HIV-related pain, fibromyalgia syndrome, cancer pain, inflammatory pain, acute pain, chronic pain, postoperative pain, post-extraction pain, chronic musculoskeletal pain, nociceptive pain, psychogenic pain, and menstrual pain), migraine, pruritus, lower urinary tract symptom, irritable bowel syndrome, epilepsy, restless legs syndrome, hot flash, mood disorder, and sleep disorder.
Pruritus is a troublesome symptom in many skin diseases, including inflammatory skin diseases such as atopic dermatitis, urticaria, psoriasis, eczema/dermatitis, prurigo, xeroderma, mycosis, hydroa, insect bites and stings, and drug eruption; it elicits a scratching movement and aggravates skin symptoms. Pruritus also occurs in some systemic diseases of internal medicine such as chronic kidney failure, diabetes mellitus, liver diseases such as cirrhosis, thyroid dysfunction, malignant tumor, leukemia, and multiple sclerosis. It is known that itching in urticaria, a typical example of pruritic skin disease, is caused mainly by histamine; however, the pathogenesis of other types of pruritus have not been clear. Antiallergic, antihistamine, and topical steroid are among the drugs currently in use for the treatment of pruritus. However, these drugs are not effective for all types of pruritus. Topical steroid agents are effective, but it is well known that they accompany side effects after long-term use. Under these circumstances, there is a demand for improved therapeutic and/or preventive agents for pruritus.
On the other hand, compound (A) is a known example of a tricyclic compound that has a phosphodiesterase (PDE) V inhibitory activity (see Patent Document 1). Among other examples, Compound (B) is known as a bicyclic pyrimidine derivative with a tachykinin receptor antagonistic activity (see Patent Document 2).
    (Me means CH3)    Patent Document 1: WO01/83460    Patent Document 2: WO03/080619